Alzheimer's disease (AD) is the most common cause of senile dementia and Amyloid Precursor Protein (APP) is intimately associated with the disease etiology. Our long term Aim is to identify the function of APP so its role in the neurodegenerative disease can be better understood. APP, a trans-membrane protein, is processed to generate smaller fragments including the toxic Abeta peptide and the APP intracellular domain (AICD) which is released in the cytoplasm. Our specific hypothesis is that AICD alters intracellular signaling pathways and contributes to AD pathology. We base this hypothesis on the observations that 1) AICD possesses transcriptional regulatory activity and perturbs multiple signaling pathways, 2) AICD in vitro induces expression of GSK-3beta and causes cell death by apoptosis, 3) The AICD transgenic mice show activation of GSK-3beta and phosphorylation of a downstream protein and both these events are found in AD brain, and 4) we show that AICD levels are higher in an 'APPswe'expressing transgenic mouse model of AD. Based on these observations the experimental focus of this proposal is on characterizing the potential role of AICD in AD pathology. The Specific Aims are to: 1) Evaluate the effects of AICD in vivo. AICD is shown to cause deleterious effects in vitro and we will determine whether these effects also occur in vivo in the AICD transgenic mice that we have created. 2) Examine the relevance of AICD to AD pathology by characterizing AICD in normal and AD brain. We recently showed that endogenous AICD can be detected in normal mouse brains and presented preliminary data to show that AICD levels are higher in mouse models of Alzheimer's disease. We will extend these findings by further characterizing the endogenous AICD and normal and AD brains. 3) Generate and study AICD50 transgenic mice. The processing of APP may give rise to two AICD fragments- AICD59 and AICD50. We will generate AICD50 mice the way we created AICD59 mice and determine in vivo to what extent AICD50 displays biological effects of AICD59. The significance of the proposal is that by accomplishing these studies, we expect to have a better understanding of the contribution of AICD to AD pathology. This proposal has relevance with respect to the development of new therapeutic strategies by identifying the signaling pathways that are perturbed in Alzheimer's disease.